Clinical and Genetic Risk Factors for Acute Incident Venous Thromboembolism in Ambulatory Patients With COVID-19

  1. JunQing Xie
  2. Albert Prats-Uribe
  3. Qi Feng
  4. YunHe Wang
  5. Dipender Gill
  6. Roger Paredes
  7. Dani Prieto-Alhambra

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Abstract

The risk of venous thromboembolism (VTE) in ambulatory COVID-19 is controversial. In addition, the association of vaccination with COVID-19–related VTE and relevant clinical and genetic risk factors remain to be elucidated.

Objective

To quantify the association between ambulatory COVID-19 and short-term risk of VTE, study the potential protective role of vaccination, and investigate clinical and genetic risk factors for post–COVID-19 VTE.

Design, Setting, and Participants

This population-based cohort study of patients with COVID-19 from UK Biobank included participants with SARS-CoV-2 infection that was confirmed by a positive polymerase chain test reaction result between March 1, 2020, and September 3, 2021, who were then propensity score matched to COVID-19–naive people during the same period. Participants with a history of VTE who used antithrombotic drugs (1 year before index dates) or tested positive in hospital were excluded.

Exposures

First infection with SARS-CoV-2, age, sex, ethnicity, socioeconomic status, obesity, vaccination status, and inherited thrombophilia.

Main Outcomes and Measures

The primary outcome was a composite VTE, including deep vein thrombosis or pulmonary embolism, which occurred 30 days after the infection. Hazard ratios (HRs) with 95% CIs were calculated using cause-specific Cox models.

Results

In 18 818 outpatients with COVID-19 (10 580 women [56.2%]; mean [SD] age, 64.3 [8.0] years) and 93 179 matched uninfected participants (52 177 women [56.0%]; mean [SD] age, 64.3 [7.9] years), the infection was associated with an increased risk of VTE in 30 days (incidence rate of 50.99 and 2.37 per 1000 person-years for infected and uninfected people, respectively; HR, 21.42; 95% CI, 12.63-36.31). However, risk was substantially attenuated among the fully vaccinated (HR, 5.95; 95% CI, 1.82-19.5; interaction P  = .02). In patients with COVID-19, older age, male sex, and obesity were independently associated with higher risk, with adjusted HRs of 1.87 (95% CI, 1.50-2.33) per 10 years, 1.69 (95% CI, 1.30-2.19), and 1.83 (95% CI, 1.28-2.61), respectively. Further, inherited thrombophilia was associated with an HR of 2.05 (95% CI, 1.15-3.66) for post–COVID-19 VTE.

Conclusions and Relevance

In this population-based cohort study of patients with COVID-19, ambulatory COVID-19 was associated with a substantially increased risk of incident VTE, but this risk was greatly reduced in fully vaccinated people with breakthrough infection. Older age, male sex, and obesity were clinical risk factors for post–COVID-19 VTE; factor V Leiden thrombophilia was additionally associated with double the risk, comparable with the risk of 10-year aging. These findings may reinforce the need for vaccination, inform VTE risk stratification, and call for targeted VTE prophylaxis strategies for unvaccinated outpatients with COVID-19.

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  1. Version published to 10.1001/jamainternmed.2022.3858
  2. ScreenIT

    SciScore for 10.1101/2022.03.22.22272748: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsConsent: All participants provided written informed consent at the UKBB cohort recruitment.
    IACUC: This study received ethical approval from UKBB Ethics Advisory Committee (EAC) and was performed under the application of 65397.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Genetic data management and quality controls were performed using Plink 1.9.20
    Plink
    suggested: (PLINK, RRID:SCR_001757)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study also has some limitations. Residual confounding cannot be ruled out in this observational study, although robust statistical approaches for causal inference was applied, including PS matching and knowledge-driven negative control analyses. Participants recruited in UKBB might not fully represent the general population and were likely healthier. Although those Covid-19 participants were from non-hospital settings, they were likely to be symptomatic and more severe cases. The extent to which asymptomatic infection is associated with VTE risk warrants further investigation. Finally, the estimates from our analyses were an average and mixed effect of several SARS-CoV-2 strains, which should be cautiously extrapolated to novel variants, such as Omicron. Community-based ambulatory Covid-19 is associated with a striking 20-fold excess risk of VTE. This risk was much higher among unvaccinated individuals, and increased with older age, in men, and in patients with obesity. Inherited thrombophilia further doubled VTE risk, comparable to a 10-year ageing effect. Our findings call for targeted prevention strategies for post-Covid VTE in outpatient settings, and suggest an aetiological role of inherited thrombophilia. The clinical utility of genetic testing to stratify infected patients and inform personalized thromboprophylaxis warrants further research.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2022.03.22.22272748v1 on medRxiv